Pharmacologic stress is increasingly being employed as an alternative to exercise stress in patients undergoing nuclear or echocardiographic imaging for the detection of coronary artery disease. It is frequently induced with adenosine or dipyridamole in patients with suspected coronary artery disease prior to imaging with radiolabeled perfusion tracers such as .sup.201 Tl or .sup.99m Tc-sestamibi, or by echocardiography. In 1999, it is predicted that 1.7 million patients will be studied using pharmacologic stress imaging in the United States alone. The advantage of pharmacologic vasodilatation over exercise is that pharmacologic stress results in a repeatable level of coronary flow increase which is not dependent upon patient fitness and/or motivation. The sensitivity and specificity for the detection of coronary artery disease is high for both adenosine and dipyridamole stress perfusion imaging, ranging between 85-90%.
A major disadvantage of using adenosine or dipyridamole stress is that there is an unusually high incidence of adverse side effects with both of these vasodilators. In one prospective study of 9,256 patients that underwent adenosine stress radionuclide imaging, 82% experienced adverse side effects (M. D. Cequiera et al., J. Am. Coll. Cardiol., 23, 384 (1994)). The most common side effects were flushing (37%), chest pain (35%), shortness of breath or dyspnea (35%), headache (14%), ECG changes (9%), and A-V conduction block (8%). A similar side effect profile has been reported for dipyridamole. In a study by A. Ranhosky et al. (Circulation, 81, 1205 (1990)) with 3,911 patients receiving dipyridamole, 19.7% experienced chest pain, 12% had headaches, and 8% had ST-segment changes on their ECG. In addition to these side effects, a substantial number of patients experience a marked decrease in blood pressure during the administration of these vasodilators. In another 3,715 patients receiving dipyridamole, the mean systolic blood pressure fell by 14 mm Hg with 11% of the patients demonstrating a &gt;20% drop in systolic blood pressure (J. Lette et al., J. Nucl. Cardiol., 2, 3 (1995)).
Whereas the desired coronary vasodilatation is mediated by the stimulation of the adenosine A.sub.2A receptor by adenosine, most of the side effects are caused by stimulation of the other three adenosine receptor subtypes: A.sub.1, A.sub.2 B, and A.sub.3. While a pre-treatment strategy with an adenosine receptor antagonist may reduce some side effects and improve patient comfort and safety, a simpler strategy would be to design a vasodilator that has little or no affinity for the adenosine A.sub.1, A.sub.2B or A.sub.3 receptor subtypes, but that selectively stimulates the A.sub.2A receptors. In fact, there has been progressive development of compounds that are more and more potent and/or selective as agonists of A.sub.2A adenosine receptors (AR) based on radioligand binding assays and physiological responses. Initially, compounds with little or no selectivity for A.sub.2A receptors were developed, such as adenosine itself or 5'-carboxamides of adenosine, such as 5'-N-ethylcarboxamidoadenosine (NECA) (B. N. Cronstein et al., J. Immnol., 135, 1366 (1985)). Later, it was shown that addition of 2-alkylamino substituents increased potency and selectivity, e.g., CV1808 and CGS21680 (M. F. Jarvis et al., J. Pharmacol. Exp. Ther., 251, 888 (1989)). 2-Alkoxy-substituted adenosine derivatives such as WRC-0090 are even more potent and selective as agonists at the coronary artery A.sub.2A receptor (M. Ueeda et al., J. Med. Chem., 34, 1334 (1991)).
Olsson et al. (U.S. Pat. No. 5,140,015) disclose certain adenosine A.sub.2 receptor agonists of formula: ##STR1##
wherein C(X)BR.sub.2 can be CH.sub.2 OH and R.sub.1 can be alkyl- or alkoxyalkyl. The compounds are disclosed to be useful as vasodilators or an antihypertensives. PA1 wherein R and X are as described in the patent. PA1 wherein Rib is ribosyl, R.sub.1 can be H and R.sub.2 can be cycloalkyl. The compounds are disclosed to be useful for treating hypertension, atherosclerosis and as vasodilators. PA1 (1) administering an amount of one or more compounds of the general formula (I): ##STR4## PA1 (2) performing a technique on said mammal to detect and/or determine the severity of said coronary artery stenosis.
Linden et al. (U.S. Pat. No. 5,877,180) is based on the discovery that certain inflammatory diseases, such as arthritis and asthma, may be effectively treated by the administration of compounds which are selective agonists of A.sub.2A adenosine receptors, preferably in combination with a Type IV phosphodiesterase inhibitor. An embodiment of the Linden et al. invention provides a method for treating inflammatory diseases by administering an effective amount of an A.sub.2A adenosine receptor of the following formula: ##STR2##
Mohiuddin et al. (U.S. Pat. No. 5,070,877) discloses the use of the relatively nonspecific adenosine analog, 2-chloroadenosine (Cl-Ado), as a pharmacological stressor. However, the Cl-Ado analog is actually a more potent activator of A.sub.1 adenosine receptors than of A.sub.2A adenosine receptors and, thus, is likely to cause side effects due to activation of A.sub.1 receptors on cardiac muscle and other tissues causing effects such as "heart block."
G. Cristalli (U.S. Pat. No. 5,593,975) discloses 2-arylethynyl, 2-cycloalkylethynyl or 2-hydroxyalkylethynyl derivatives, wherein the riboside residue is substituted by carboxy amino, or substituted carboxy amino (R.sub.3 HNC(O)--). 2-Alkynylpurine derivatives have also been disclosed in Miyasaka et al. (U.S. Pat. No. 4,956,345), wherein the 2-alkynyl group is substituted with (C.sub.3 -C.sub.16)alkyl. The '975 compounds are disclosed to be vasodilators and to inhibit platelet aggregation, and thus to be useful as anti-ischeric, anti-atherosclerosis and anti-hypertensive agents.
R. A. Olsson et al. (U.S. Pat. No. 5,278,150) disclose selective adenosine A.sub.2 receptor agonists of the formula: ##STR3##
These 2-alklylhydrazino adenosine derivatives, such as 2-cyclohexyl methylidene hydrainoadenosine (WRC-0474), have also been evaluated as agonists at the coronary artery A.sub.2A receptor (K. Niiya et al., J. Med. Chem., 35, 4557 (1992)). WRC-0474 has further been evaluated in the dog model for use in pharmacological stress thallium imaging. See, D. K. Glover et al., Circulation, 94, 1726 (1996).
Thus, a continuing need exists for selective A.sub.2 adenosine receptor agonists useful for use as pharmacological stressors in stress imaging or in other ventricular function imaging techniques, that preferably have reduced side effects, while being chemically stable and short-acting.